WO2017088950A1 - Bêta-hydroxy-cétone utilisée comme principe actif à usage topique pour la prévention ou le traitement de photodermatoses - Google Patents

Bêta-hydroxy-cétone utilisée comme principe actif à usage topique pour la prévention ou le traitement de photodermatoses Download PDF

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Publication number
WO2017088950A1
WO2017088950A1 PCT/EP2016/001815 EP2016001815W WO2017088950A1 WO 2017088950 A1 WO2017088950 A1 WO 2017088950A1 EP 2016001815 W EP2016001815 W EP 2016001815W WO 2017088950 A1 WO2017088950 A1 WO 2017088950A1
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WO
WIPO (PCT)
Prior art keywords
branched
straight
formula
chain
prevention
Prior art date
Application number
PCT/EP2016/001815
Other languages
German (de)
English (en)
Inventor
Christophe Carola
Lilia Heider
Marina LEFORT
Hansjuergen Driller
Original Assignee
Merck Patent Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to US15/778,747 priority Critical patent/US10660867B2/en
Priority to EP16794515.3A priority patent/EP3380093B1/fr
Priority to ES16794515T priority patent/ES2879819T3/es
Publication of WO2017088950A1 publication Critical patent/WO2017088950A1/fr
Priority to US16/849,115 priority patent/US20200237685A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • ß-hydroxy ketones as topical agents for the prevention or treatment of photodermatoses
  • the present invention relates to specific ⁇ -hydroxy ketones of formula (I) for use in the prevention and / or treatment of
  • Photodermatoses in particular polymorphic photodermatosis.
  • Photodermatoses are skin diseases that result from exposure to radiation, preferably UVA, UVB and / or visual radiation, which may be from natural or artificial sources.
  • sunburn photodermatoses include, for example, skin lesions due to phototoxic reaction or photoallergic response to drugs or
  • the polymorphic light dermatosis is a very common
  • Photodermatosis where it is believed that the action of UVA radiation in particular is responsible. Approximately 11-21% Northern Europeans are likely to be affected by these skin conditions. The polymorphic light dermatosis usually occurs in spring or early summer after the first exposure to the sun. In recent sun exposure, the flare over the summer usually weaker.
  • the skin changes occur mainly on the outsides of the
  • Skin manifestations can take a variety of forms (e.g., redness, blisters, nodules, oozing skin defects, skin thickening). However, they are usually limited to one person in one of these forms. There is always a strong itching.
  • sunscreens are described, for example, in A. Fourtanier et al, Photodermatoloty, Photoimmunology & Photomedicine 2008, 24, 164-174.
  • sunscreens contain, in addition to the UVA filters, antioxidants such as alpha-glucosylrutin, as described in IM Hadshiew et al, Photodermatoloty, Photoimmunology & Photomedicine 2004, 20 (4), 200-4.
  • antioxidants such as alpha-glucosylrutin, as described in IM Hadshiew et al, Photodermatoloty, Photoimmunology & Photomedicine 2004, 20 (4), 200-4.
  • topical preparations containing corticosteroids are used or a photo (chemo) therapy is performed.
  • a first subject of the invention are therefore compounds of the formula (I)
  • R 1 to R 0 are each independently H, straight-chain or branched C 1 - to C 20 -alkyl group, straight-chain or branched C 1 - to C 20 -alkoxy group or straight-chain or branched C 1 - to C 20 -dialkylamino group,
  • Photodermatoses preferred for use in the prevention and / or treatment of polymorphic photodermatosis.
  • Another object of the invention is the use of a
  • R 1 to R 10 are each independently H, straight-chain or branched C 1 to C 20 alkyl, straight-chain or branched C 1 to C 20 alkoxy group or straight-chain or branched C 1 to C 20 dialkylamino group, as active ingredient in a cosmetic
  • 2007/121845 includes other compounds not covered by formula (I) as previously described. In general, all compounds known from WO 2007/121845 are described as antioxidants. As described there with reference to CD Römpp Chemie Lexikon - Version 1.0, Stuttgart / New York: Georg Thieme Verlag 1995, it is
  • Oxidative processes inhibit or prevent changes in the substances to be protected. They therefore work
  • R 1 to R 10 each independently of one another denote H, straight-chain or branched C 1 - to C 20 -alkyl group, straight-chain or branched C 1 - to C 20 -alkoxy group or straight-chain or branched C 1 - to C 20 -dialkylamino group are not UV filters, ie they show no UV absorption.
  • the absorption behavior is representative of the
  • Diketone derivatives act. The action of sunlight releases the
  • UVA filter formed by decomposition of 3- (4-tert-butylphenyl) -3-hydroxy-1- (4-methoxyphenyl) -propan-1-one under the influence of UV light is only 0.1% by weight.
  • Such a portion of a UVA filter does not provide efficient UVA protection and, therefore, may not account for the positive results of the in vivo study and the efficacy against photodermatosis, particularly polymorphic photodermatosis.
  • the compounds of formula (I) prevent the appearance of photodermatosis, in particular polymorphic light dermatosis. Accordingly, the second medical or the second non-medical use of the compounds of formula (I) is preferably a prevention of photodermatoses, more preferably one
  • the compounds of the formula (I) which are active as such can convert into a UVA filter after decomposition by the action of sunlight, and thus even after their own decomposition Sun exposure, further support a prevention of photodermatosis.
  • the substituents R 1 to R 10 may each independently be H, straight-chain or branched C 1 to C 20 alkyl group, straight-chain or branched C 1 to C 20 alkoxy group or straight-chain or branched C 1 to C 20 dialkylamino group.
  • an alkyl group is not specified, it is a straight-chain alkyl group.
  • Straight or branched chain dialkylamino groups having from 1 to 4, 1 to 8, 1 to 12 or 1 to 20 carbon atoms are of the formula N (C P H2 P + i) 2 with p are each independently 1, 2, 3 or 4, or 1, 2, 3, 4, 5, 6, 7 or 8, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, for example
  • the alkyl groups are each independently straight-chain or branched and preferably have 1 to 12 C atoms, particularly preferably 1 to 4 C atoms.
  • the alkoxy groups are each independently straight-chain or branched and preferably have 1 to 12 C-atoms, particularly preferably 1 to 4 C-atoms.
  • the diaminoalkyl groups are each independently straight-chain or branched and preferably have 1 to 12 C-atoms, particularly preferably 1 to 4 C-atoms.
  • Preferred compounds of the formula (I) are compounds in which R, R 2 , R 4 , R 5 , R 6 , R 7 , R 9 and R 10 are H and R 3 and R 8 are each
  • Particularly preferred compounds of the formula (I) are compounds in which R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 9 and R 10 are H and R 3 and R 8 are each independently straight-chain or branched C 1 to C 4 alkyl group or straight-chain or branched C 1 to C 4 alkoxy group.
  • Very particularly preferred compounds of the formula (I) are 3- (4-tert-butylphenyl) -3-hydroxy-1- (4-methoxyphenyl) propan-1-one, 1- (4-tert-butyl - phenyl) -3-hydroxy-3- (4-methoxy-phenyl) -propan-1-one or their
  • Another object of the invention are therefore compounds of formula (I), as described above, wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 R 9 and R 10 is H and R 3 and R 8 are each independently of one another represent straight-chain or branched C 1 - to C 12 -alkyl group or straight-chain or branched C 1 - to C 12 -alkoxy group, for use in the prevention and / or treatment of photodermatoses, in particular in US Pat
  • Another object of the invention are therefore compounds of formula (I), as described above, wherein R ⁇ R 2 , R 4 , R 5 , R 6 , R 7 , R 9 and R 10 is H and R 3 and R 8 are each independently of one another represent straight-chain or branched C 1 - to C 4 -alkyl group or straight-chain or branched C 1 - to C 4 -alkoxy group, for use in the prevention and / or treatment of photodermatoses, in particular in the prevention of polymorphic light dermatosis.
  • Another object of the invention are therefore the compounds 3- (4-tert-butyl-phenyl) -3-hydroxy-1 - (4-methoxyphenyl) -propan-1-one, 1- (4-tert-butyl) phenyl) -3-hydroxy-3- (4-methoxyphenyl) -propan-1-one or a mixture thereof, for use in the prevention and / or treatment of photodermatoses, in particular in the prevention of polymorphic photodermatosis.
  • Another object of the invention is therefore the use of compounds of formula (I) as active ingredient in a cosmetic
  • Another object of the invention is therefore the use of compounds of formula (I) as active ingredient in a cosmetic
  • Another object of the invention is therefore the use of the compounds 3- (4-tert-butyl-phenyl) -3-hydroxy-1- (4-methoxyphenyl) propane-1-one, 1- (4-tert-butyl) Butyl-phenyl) -3-hydroxy-3- (4-methoxyphenyl) propan-1-one or a mixture thereof as active ingredient (s) in a cosmetic preparation for the non-therapeutic treatment and / or prevention of photodermatosis, in particular for Prevention of polymorphic photodermatosis.
  • Another object of the invention is directed to a non-therapeutic method for the prevention of photodermatoses, characterized in that the skin is a cosmetic preparation
  • Another object of the invention is directed to a non-therapeutic method for the prevention of polymorphic photodermatosis, characterized in that a cosmetic preparation is applied to the skin which comprises at least one compound of the formula (I) as described above or described as preferred contains.
  • Another object of the invention is directed to a non-therapeutic method for the prevention of polymorphic photodermatosis, characterized in that a cosmetic preparation is applied to the skin, the 3- (4-tert-butyl-phenyl) -3-hydroxy-1 (4-methoxyphenyl) propan-1-one, 1- (4-tert-butylphenyl) -3-hydroxy-3- (4-methoxyphenyl) -propan-1-one or a mixture thereof, contains.
  • the type of cosmetic or pharmaceutical preparation comprising at least one compound of the formula (I), as described above or preferably described, is not restricted in this case. Suitable preparations are known, for example, from WO 2007/121845, WO 2011/141111 and DE 102012016960 A1.
  • the compounds of the formula (I) as described or preferred described above are preferably used in the second non-medical use or in the second medical use in an amount of 1 to 10% by weight, preferably 2 to 5% by weight incorporated the corresponding preparations.
  • Particularly suitable active ingredients for combination are, for example, 1- (4-methoxyphenyl) -3- (4-tert-butylphenyl) -1,3-propanedione (Eusolex® 9020 (Merck)), Escamule (Mexoryl® SX (from Chimex) .
  • Broadband filters such as uncoated or coated titanium dioxides
  • Zinc oxides or particulate filters such as Tinosorb® S, Tinosorb® M or Tris Biphenyl Triazine (TBPT), sold by BASF, optionally in combination with suitable antioxidants such as a-glucosylrutin, isoquercetin or 2- (4-hydroxy-3,5 -dimethoxybenzy) malonic acid bis (2-ethylhexyl) ester (RonaCare® AP (Merck)).
  • suitable antioxidants such as a-glucosylrutin, isoquercetin or 2- (4-hydroxy-3,5 -dimethoxybenzy) malonic acid bis (2-ethylhexyl) ester (RonaCare® AP (Merck)).
  • a comparative study with positive control was performed on 6 subjects with known PLE syndrome. The study was conducted in Germany over a period of 5 days in April. The positive control was untreated, irradiated skin. It was irradiated with 100% UVA light, in a sub-erythemal dose, which was determined individually. The preparation was applied daily to half of the Vietnameselleté (2 mg / cm 2 ).
  • the measurements were performed twice a day, 10 min. after application of the preparation and directly after irradiation.
  • Table 1 shows skin reactions under UVA irradiation in untreated skin: Family
  • Table 2 shows skin reactions under UVA irradiation in treated skin:
  • FIG. 1 shows the absorption spectrum of the compound 3- (4-tert-butylphenyl) -3-hydroxy-1- (4-methoxyphenyl) -propan-1-one.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)

Abstract

La présente invention concerne une ß-hydroxy-cétone spéciale de formule (I) destinée à la prévention et/ou au traitement de photodermatoses, ainsi que l'utilisation de ß-hydroxy-cétones spéciales de formule (I) comme principe actif dans des compositions topiques destinées à la prévention et/ou au traitement non thérapeutique de photodermatoses, notamment de la photodermatose polymorphe.
PCT/EP2016/001815 2015-11-27 2016-11-02 Bêta-hydroxy-cétone utilisée comme principe actif à usage topique pour la prévention ou le traitement de photodermatoses WO2017088950A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US15/778,747 US10660867B2 (en) 2015-11-27 2016-11-02 Beta-hydroxyketones as topical active ingredients for the prevention or treatment of photodermatoses
EP16794515.3A EP3380093B1 (fr) 2015-11-27 2016-11-02 Bêta-hydroxy-cétone utilisée comme principe actif à usage topique pour la prévention ou le traitement de photodermatoses
ES16794515T ES2879819T3 (es) 2015-11-27 2016-11-02 ß-Hidroxicetonas como principios activos tópicos para la prevención o el tratamiento de fotodermatosis.
US16/849,115 US20200237685A1 (en) 2015-11-27 2020-04-15 Beta-Hydroxyketones as topical active ingredients for the prevention or treatment of photodermatoses

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP15196821 2015-11-27
EP15196821.1 2015-11-27

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US15/778,747 A-371-Of-International US10660867B2 (en) 2015-11-27 2016-11-02 Beta-hydroxyketones as topical active ingredients for the prevention or treatment of photodermatoses
US16/849,115 Division US20200237685A1 (en) 2015-11-27 2020-04-15 Beta-Hydroxyketones as topical active ingredients for the prevention or treatment of photodermatoses

Publications (1)

Publication Number Publication Date
WO2017088950A1 true WO2017088950A1 (fr) 2017-06-01

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Country Status (4)

Country Link
US (2) US10660867B2 (fr)
EP (1) EP3380093B1 (fr)
ES (1) ES2879819T3 (fr)
WO (1) WO2017088950A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102006019044A1 (de) * 2006-04-25 2007-10-31 Merck Patent Gmbh Antioxidantien
WO2011141111A2 (fr) 2010-05-12 2011-11-17 Merck Patent Gmbh Triazines utilisées comme accélérateurs de réaction
DE102010055084A1 (de) 2010-12-18 2012-06-21 Merck Patent Gmbh Selektive Reduktion von 1,3-Diketonen
WO2013045016A2 (fr) * 2011-09-29 2013-04-04 Merck Patent Gmbh Oxydes de phosphane en tant qu'accélérateurs de réaction
DE102012016960A1 (de) 2012-08-28 2014-03-06 Merck Patent Gmbh Aminoester von Aminosäuren als Reaktionsbeschleuniger

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102006019044A1 (de) * 2006-04-25 2007-10-31 Merck Patent Gmbh Antioxidantien
WO2007121845A1 (fr) 2006-04-25 2007-11-01 Merck Patent Gmbh Antioxydants
WO2011141111A2 (fr) 2010-05-12 2011-11-17 Merck Patent Gmbh Triazines utilisées comme accélérateurs de réaction
DE102010055084A1 (de) 2010-12-18 2012-06-21 Merck Patent Gmbh Selektive Reduktion von 1,3-Diketonen
WO2013045016A2 (fr) * 2011-09-29 2013-04-04 Merck Patent Gmbh Oxydes de phosphane en tant qu'accélérateurs de réaction
DE102012016960A1 (de) 2012-08-28 2014-03-06 Merck Patent Gmbh Aminoester von Aminosäuren als Reaktionsbeschleuniger

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"CD Römpp Chemie Lexikon - Version 1.0", 1995, GEORG THIEME VERLAG
A. FOURTANIER ET AL., PHOTODERMATOLOTY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, vol. 24, 2008, pages 164 - 174
AIGUO HU ET AL: "Supporting Information for Ru-Catalyzed Asymmetric Hydrogenation of [alpha]-Phthalimide Ketones and 1,3-Diaryl Diketones Using 4,4'-Substituted BINAPs", ORGANIC LETTERS; VOL. 7, NO. 3, 1 January 2005 (2005-01-01), XP055334019, Retrieved from the Internet <URL:http://pubs.acs.org/doi/suppl/10.1021/ol0474812> [retrieved on 20170111] *
BAEUERLE, CELL, vol. 95, no. 6, 1998, pages 729 - 31
FUSARO R M ET AL: "Topical photoprotection for hereditary polymorphic light eruption of American Indians", JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, MOSBY, INC, US, vol. 24, no. 5, 1 May 1991 (1991-05-01), pages 744 - 746, XP025616630, ISSN: 0190-9622, [retrieved on 19910501], DOI: 10.1016/0190-9622(91)70114-H *
IM HADSHIEW ET AL., PHOTODERMATOLOTY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, vol. 20, no. 4, 2004, pages 200 - 4
K. S. RAVIKUMAR ET AL: "Diastereoselectivity in the Reduction of Acyclic Carbonyl Compounds with Diisopropoxytitanium(III) Tetrahydroborate", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 64, no. 16, 1 August 1999 (1999-08-01), pages 5841 - 5844, XP055334721, ISSN: 0022-3263, DOI: 10.1021/jo9902906 *

Also Published As

Publication number Publication date
US20200237685A1 (en) 2020-07-30
US10660867B2 (en) 2020-05-26
ES2879819T3 (es) 2021-11-23
US20180353442A1 (en) 2018-12-13
EP3380093A1 (fr) 2018-10-03
EP3380093B1 (fr) 2021-04-07

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